Researchers are rethinking their approaches to studying Parkinson’s disease in hopes that a paradigm shift may inform new therapeutic targets and strategies. An important new direction for study addresses symptoms of the disease other than those resulting from the loss of the neurotransmitter dopamine. Scientists have already discovered a wealth of information about what happens in the brain as Parkinson’s disease progresses, but very little of it has translated into effective treatments. In the past year, geneticists in Japan have uncovered several susceptibility genes for the disorder. Scientists at the Weill Cornell Medical College in New York have created what they believe is a superior animal model of Parkinson’s disease. And researchers at Harvard Medical School are bringing together data from epidemiological and evolutionary science work to investigate new treatments that may slow the disease’s progression.

What We Know—and Don’t Know

Parkinson’s disease is most easily described by its cardinal symptoms. These movement-related symptoms, including the telltale tremor, muscular rigidity, stooped posture and slowness of movement, were first described by James Parkinson in his 1817 article “An Essay on the Shaking Palsy.” Over the next two centuries, clinicians added to this early description associated effects of the disease such as sleep disturbances, depression, cognitive impairment and a variety of gastrointestinal problems.

These symptoms result primarily from the degeneration of a small but crucial group of dopamine-producing neurons in an area of the brain called the substantia nigra. When these cells die, the lack of dopamine release disrupts the synaptic functioning of the neurons in nearby areas, including the motor cortex and striatum. Parkinson’s disease is most often diagnosed when approximately 50–80 percent of these key substantia nigral neurons have been lost—and usually after symptoms are noticeable. But though scientists understand a greatdeal about this basic pathology, they are still unsure about just what causes the loss of these critical neurons.

Mahlon DeLong of Emory University is a leading expert on Parkinson’s disease. (Courtesy of Mahlon DeLong / Emory University)

Mahlon DeLong, an expert in Parkinson’s disease at Emory University, cites several mechanisms that could cause damage to dopamine neurons. “Mitochondrial dysfunction has been strongly implicated,” he said, referring to the molecules that produce energy for cells’ activity, the mitochondria. “Oxidative stress, certainly, and the release of free radicals could result in the loss of these dopamine neurons. And others have considered protein aggregation. There’s certainly evidence that amassing an abnormal amount of a protein called alpha-synuclein plays an important role.”

Many people in the early stages of the disease can be successfully treated with the dopamine precursor drug levadopa (L-DOPA), which helps the brain replace enough dopamine to function successfully. But that treatment cannot be sustained indefinitely. Over time, with the loss of more substantia nigra neurons, the drug loses its ability to produce enough of this critical neurotransmitter. What’s more, despite the great inroads into understanding the underlying molecular pathology of the disease, scientists are now learning that Parkinson’s causes damage to more than just dopamine-producing neurons.1 Areas across the brain, spinal cord and peripheral nervous system are also affected, and their decline can lead to some of the more debilitating symptoms of Parkinson’s, such as sleep disorders, propensity for falls and cognitive impairment.

Simply put, scientists now know that Parkinson’s disease is more than just a dopamine deficiency. With this newer understanding, they are reexamining their theories about the neurobiological processes underlying Parkinson’s origins and progression in hopes of finding better treatments.

Genetic Susceptibilities

Part of the difficulty in understanding Parkinson’s disease is parsing both the genetic and the environmental components of susceptibility. “About 5 to 10 percent of cases are familial,” said Tatsushi Toda, a genetic neurologist at the Kobe University Graduate School of Medicine in Japan. “A small portion of familial Parkinson’s disease is due to Mendelian inheritance, or a single-gene disorder. The rest of cases can be attributed to a multifactorial disorder comprised of what we presume are thirty to fifty susceptible genes mixed with environmental factors.”

Thus, the majority of cases of Parkinson’s disease arise from unknown causes or, as clinicians more commonly say, sporadic causes.

“It’s quite clear now that Parkinson’s is not a single disease,” DeLong said. “There are hereditary forms of the disease for which there are specific gene mutations that mean if you have the gene, you are almost certain to get it. There are cases where the disease seems to be due to environmental factors like toxins. But the vast majority of patients, we just don’t know what combination of genes and environmental factors may be at play.”

In addition, DeLong noted, atypical forms of the disease occur. Often referred to as Parkinson’s-like disorders, these include essential tremor, dementia with Lewy bodies, progressive supranuclear palsy and multiple system atrophy. DeLong and others have proposed that all of these disorders may be related, or even simply different points on a wide clinical spectrum of disease.

“It’s important to study all of these because we may find common mechanisms or pathways that these diseases share. Each of these disorders may start at a different point or have different chemical or biologic systems involved, but there may still be enough potential overlap to inform other areas,” he said.

“For example, the same gene transmitted in a family can appear as an essential tremor in some individuals and as Parkinson’s in others. That must mean that the genetic backdrop in those two family members is different enough that the gene is expressed differently. And understanding just how it is expressed differently may tell us quite a bit.”

These overlaps are driving current investigations of the genes responsible for Parkinson’s neurodegenerative effects. For example, for both Parkinson’s disease and the Parkinson’s-like dementia with Lewy bodies, researchers have found a strong association with the glucocerebrosidase (GBA) gene, a gene linked to Gaucher disease, a disorder of the body’s storage of fatty acids. Parkinson’s-like dementia with Lewy bodies is a common form of dementia characterized by the buildup of alpha-synuclein protein in neurons in the motor and memory areas of the brain and accompanied by visual hallucinations.2

In the May 2009 issue of Archives of Neurology, Toda and his colleagues demonstrated that individuals who had specific mutations of GBA were nearly thirty times more likely to develop Parkinson’s disease. In addition, individuals with these genetic variants were more likely to develop Parkinson’s at a younger age. A second study in the same issue, led by Columbia University’s Karen Marder, found an association between a mutated GBA gene and dementia with Lewy bodies.3 Since the biological changes caused by Gaucher, a singlegene disease, are fairly well documented, Toda believes that this association can provide new pathways and molecular mechanisms for researchers to examine these other disorders. It may be that doing so will provide new targets for drug therapies.

And a Dash of Environment

Other research has focused on environmental aspects. Parkinson’s disease has much higher incidence rates in industrialized countries and has been linked to a variety of external influences. For example, some clinicians hypothesize that boxers may be more likely to develop Parkinson’s disease from repeated blows to the head during their fighting careers.

In addition, excess iron exposure, cocaine use, exposure to pesticides and use of antidepressant medications have all been implicated in industrialized nations as possible triggers. But scientists do not know how these substances interact with one’s genetic makeup to increase susceptibility to the disease later in life, sometimes even decades after exposure.

“Parkinson’s is made up of much more than just our genes,” said DeLong. “Certainly there is a lot of evidence now that pesticides play some role in the development of the disease.”

Though epidemiological data have linked exposure to pesticides such as paraquat and beta-hexachlorocyclohexane (beta-HCH) to a higher risk of developing Parkinson’s, the exact mechanisms underlying the neuropathology are still under investigation, the results of which scientists hope will shed light on other etiologies.4,5

The Right Kind of Animal Model

When it comes to finding potential treatments, clinical neuroscientists are utterly dependent on good animal models to test their theories. But to date, a truly analogous Parkinson’s disease animal model has not been developed. Part of that stems from the fact that Parkinson’s has such potentially varied origins. Single gene knock-out models—animals bred to have a specific gene missing—have proven useful in offering new treatment directions for diseases such as diabetes and cancer but, to date, no single model has been able to capture all of Parkinson’s tell-tale symptoms.

In the July 2009 issue of Nature Neuroscience, Chenjian Li of Weill Cornell Medical College, introduced a new animal model, a LRRK2 transgenic mouse, that he argues is a more valid model for the human disease.6,7

LRRK2 has been implicated as a gene of interest in the development of Parkinson’s disease in dozens of studies. And Li’s group mutated it in such a way that it overexpressed its related protein, leading to a model that demonstrates Parkinson’s most commonsymptoms for the first time.

“It’s been difficult to get really good animal models that really mimic the disease,” said M. Flint Beal, a neurologist also at the Weill Cornell Medical College and a coauthor on the paper. In particular, he notes, previous models have not shown the typical Parkinson’s phenotype including symptoms like slowness of movement or defects in dopamine release.

M. Flint Beal of Weill Cornell Medical College says it is difficult to find animal models that thoroughly mimic Parkinson’s disease. A paper published by Chenjian Li introduced a mouse model that is more congruent with the disorder. (M. Flint Beal / Weill Cornell Medical College)

“We were able to create a unique model of Parkinson’s disease,” says Li. “Not only does it show an age-dependent motor deficit like you see in human Parkinson’s but that deficit can be rescued with levadopa treatment – something you also see in the human form of the disease. Plus, you also see dopamine transmission problems as well as axonal degeneration in the dopaminergic system.” Li states that though it is not a perfect replica of the human disease, it is a big step forward from previous genetic models.

And why is a better model so important? Beal believes that models that better imitate typical Parkinson’s disease may offer us a clean slate of sorts. Previous pathways of interest or potential therapies that failed to yield results in animal trials may have done so not because they were wrong but because the model was not comparable enough to the human disease.

“With better models, we can go back and try again,” Beal says. “This is a superior model based on a known genetic defect in Parkinson’s. It really gives us a powerful tool to investigate potential therapies.”

Li agrees and takes it a step further. “When you have a good model, it’s almost as if you are setting up a stage. And on that stage you can perform different shows,” he says. “On one side, we can use a model like this to understand all the details of the mechanisms underlying the disease pathogenesis. But it is also a good stage for testing drug candidates. With the right models, we have the potential to serve both the scientific understanding and the pharmacological development sides of things.”

Michael Schwarzschild, a Parkinson’s researcher at Harvard Medical School, also thinks that there is value in newer, better animal models.“A good model is one that predicts the disease and things that will treat the disease. And, as we’ve learned, you don’t know whether it’s really predictive until you go to a human clinical trial,” he said. “It’s good that we are questioning old models and thinking about how to create better ones. They may offer us some good bets for potential human treatments down the line.”

The Power of Antioxidants—and Converging Evidence

Some researchers hypothesize that oxidative stress, or the accumulation of destructive free radical molecules due to an imbalance in the brain’s oxygen levels, may trigger specific cellular processes that result in the development of Parkinson’s disease. The clumping of a protein called alpha-synuclein in memory and motor areas of the brain; malfunction in neurons’ energy-producing apparatus, the mitochondria; and good old-fashioned inflammation have all been implicated in the death of dopamine-producing neurons. And scientists suspect that these three activities may be somehow related. Though the mechanism that connects them is, as yet, unknown, many suggest that oxidative stress may be the process that triggers it, and as such, sporadic Parkinson’s progression.

“Oxidative damage [the damage to neurons from oxidative stress] is such a prominent mechanism for brain cell degeneration. You see it in Alzheimer’s, Parkinson’s and other neurodegenerative disorders,” said Schwarzschild. “So it makes sense that an antioxidant may help in slowing the progression of the disease.” And one such antioxidant of interest is the purine urate. Purines are basic nitrogen-containing compounds that provide building blocks for many other significant biological substances. For example, DNA and RNA contain the nucleobases adenine and guanine, both of which are purines. Urate is another member of the purine family—the end result of purine metabolism in the body—and is believed to work as an antioxidant, combating the effects of oxidative stress on cells throughout the body.

Schwarzschild collaborated with Harvard School of Public Health’s Alberto Ascherio after seeing the epidemiologist’s work identifying urate as a predictor of whether an individual would develop Parkinson’s disease later in life.

“Our clues have come about somewhat uniquely by working at the interface of basic science and epidemiology,” he said. “Ascherio and his colleagues linked urate to a reduced risk of getting Parkinson’s disease. And so we wondered if somehow these compounds were neuroprotective.”8

Schwarzschild’s curiosity about urate was also fueled by some interesting evolutionary data: humans and apes are missing the gene that breaks down urate in the body.

“Multiple mutations in this gene appear to have taken place millions of years ago in separate lines of primate evolution suggesting there was some selective advantage to having higher levels of urate circulating in human ancestors. Maybe it’s because urate can play a protective role in our bodies including our brains,” he said.

In the June 2008 Archives of Neurology, Schwarzschild et al. looked at the urate levels in 804 individuals with early-stage Parkinson’s disease.9 The results were striking.

“We found that individuals with higher rates of urate are not only less likely to develop Parkinson’s but, if they do get the disease, show slower rates of clinical progression,” said Schwarzschild. “This molecule might not only be useful to help predict who will get the disease but also who will do better with the disease if they already have it.”

Michael Schwarzschild of Harvard Medical School collaborated with Albert Ascherio of the Harvard School of Public Health to determine whether the concentration of urate in the blood predicts the likelihood of developing Parkinson’s disease. After baseline urate levels were calculated, participants in the study were tested over a period of two years. The end point was clinical disability sufficient to require dopaminergic therapy. In both men and women who went on to develop PD, participants with higher levels of urate approached the end point at a slower rate than those with a lower level of urate. (Copyright American Medical Association, Archives of Neurology. 2008 65(6):720.)

Although Schwarzschild cautions that the association found does not imply causality, he hypothesizes that urate protects the dopamine neurons in the substantia nigra by preventing further oxidative damage. He and his colleagues are now in the beginning stages of a human clinical trial to elevate urate levels in Parkinson’s patients to see whether it improves disease outcomes.

Healthy vitamin D levels have also been linked to lower rates of Parkinson’s. Vitamin D had already been shown to have an antiinflammatory effect in conditions from cancer to heart disease. Back in 2007, researchers at the Susan Lehman Cullman Laboratory for Cancer Research at Rutgers University hypothesized that vitaminD deficiencies played a role in the prevalence of Parkinson’s.10 And subsequent epidemiological data now suggest that they may be right.

DeLong and colleagues at Emory University compared vitamin D levels in patients with Parkinson’s disease, those with Alzheimer’s disease and individuals who were healthy in a study published in the October 2008 issue of Archives of Neurology. The researchers showed that vitamin D levels were not only significantly lower in Parkinson’s patients than in the healthy group but also lower than in patients with Alzheimer’s disease.11 DeLong warns that the data are preliminary and that there’s still a lot to understand about the role of vitamin D, but he plans to look at the clinical effects of vitamin D and Parkinson’s disease.

“Vitamin D is one of those neglected areas,” said DeLong. “We’re now doing a trial to see if treating the patient’s vitamin D deficiency has any effect on the symptoms or the progression of the disease.”

New Directions From Paradigm Shifts

Although the majority of Parkinson’s researchers are seeking the causes of neuronal degeneration, Bryce Vissel and his colleagues at the Garvan Institute in Sydney, Australia, are focusing their efforts on neurogenesis (see chapter 6, “Neuroprotection”).

“We have a perception that we clearly understand the fundamental underlying pathology of Parkinson’s—and that’s the loss of those dopamine nerve cells,” Vissel said. “But perhaps it’s not the loss of the cells that is as important as an inability to regenerate them.”

Vissel argues that the fact that an exposure to a toxin may cause Parkinson’s disease ten to fifteen years later in life gives us a mystery to be solved. It may be that Parkinson’s triggers an immune inflammation response that contributes to cell death and then prevents nerve cell regeneration.

In a study published in the June 2009 issue of Stem Cells, Vissel and his collaborators demonstrated in an animal model that the brain releases a chemical called activin A that helps to repair brain cells after damage due to injection of kainic acid, an excitotoxic chemical that causes a toxic glutamate cascade and, as such, widespread cell damage and death.12 This natural neuron regenerator works by inhibiting inflammation. Vissel argues that a better understanding of this natural neural repair process may help direct scientists to novel treatments that may prevent or slow the progression of Parkinson’s disease.

But it may also help to look beyond the neurons to better understand neuronal regeneration. Yuet Wai Kan from the University of California, San Francisco and Richard Smeyne from St. Jude Children’s Research Hospital in Memphis, Tennessee, have found evidence that a chemical released by astrocytes, a type of supportive glial cell in the brain, called Nrf2, may protect neurons from Parkinsonian neurodegeneration.13 When oxidative stress causes inflammation in the brain, the astrocytes attempt to mitigate it by releasing Nrf2. Glial cells may also provide researchers with new directions for Parkinson’s treatment.

The Best Treatments

Individuals in the early stages of Parkinson’s disease are most commonly treated with dopamine agonist drugs—that is, drugs that stimulate the same receptors as dopamine itself—and have the benefit of postponing levodopa therapy, which can cause some troubling side effects. Anecdotal evidence has suggested that these dopamine agonist drugs may cause compulsive gambling and hypersexuality in some patients, and recent work is suggesting that the problem may be more widespread than initially thought.

In a study published in the April 2009 issue of Mayo ClinicProceedings, J. Michael Bostwick and colleagues examined patients in the clinic’s large patient database to see how common these side effects were.14 After looking at the data on nearly three hundred Parkinson’s patients, they found that 18.4 percent of those taking dopamine agonist drugs alone were experiencing compulsive gambling and hypersexuality, some to the point that doctors were treating the patients as if they had a separate psychiatric disorder. The same effects were not seen in those patients who were prescribed different drug therapies for their Parkinson’s disease. Even more telling, once the drug therapy was stopped in these patients, the behaviors abated.

“There are so many areas in the brain that are directly affected by dopamine,” said DeLong. “And we’re only now becoming aware that these kinds of drugs are causing these very severe, very debilitating effects. These patients will gamble away their savings, their houses, and they manage to keep it all very secret. Doctors need to be more aware of these possibilities and really keep an eye on how their patients are doing when on these drugs.”

In the past few years, deep brain stimulation (DBS), a procedure that involves an implanted device delivering steady electrical current to the brain, has made headlines for its treatment of advanced Parkinson’s disease (see chapter 2, “Deep Brain Stimulation”).

Thus far, however, the risks involved with such an invasive treatment have caused several clinicians to choose to treat older patients with drugs instead of DBS. Some question whether the benefits would outweigh the risks in patients older than age seventy.

But Frances Weaver, a physician at the Hines Veterans Administration Hospital in Illinois, and her colleagues compared the efficacy of DBS versus medical therapies in both younger and older patients. In a study published in the January 7, 2009, issue of the Journal of the American Medical Association, the group found that patients treated with DBS had better outcomes in both motor function and quality of life six months after treatment.15

On the other hand, they also found a small decrease in neurocognitive function in the DBS group and a higher incidence of adverse effects such as infections. Nevertheless, the researchers concluded that DBS was a more effective treatment for Parkinson’s symptoms than the most common medical therapies.

It is becoming more apparent that a true understanding of Parkinson’s requires more than just the study of dopamine deficiency. And with paradigm shifts offering new directions in the study of the disease’s etiology, most clinicians still share the same goal—to find ways to slow the progression of the disease. DeLong emphasizes that Parkinson’s treatment requires many new and better therapies to offer true relief to patients.

“The disease is more than just its cardinal, core features,” said DeLong. “Its fellow travelers play a huge role: the difficulty swallowing, the drooling, the mood disturbances, the autonomic nervous system impairment, the GI problems. Treating Parkinson’s means treating all of these. And to address them all comprehensively, we need to treat the mechanism underlying them all and treat not the symptoms but the disease progression.”